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MitoPedia: Respiratory control ratios
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Term | Abbreviation | Description |
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Biochemical coupling efficiency | j_{≈P} or j_{≈E} | The biochemical coupling efficiency may be expressed as the OXPHOS-coupling efficiency, j_{≈P} = (P-L)/P = 1-L/P, or ET-coupling efficiency, j_{≈E} = (E-L)/E = 1-L/E, which are equivalent at zero excess E-P capacity (ExP = E-P = 0). |
CI control ratio | N/NS; CI/CI&II | See N/NS pathway control ratio |
CII control ratio | S/NS; CII/CI&II | See S/NS pathway control ratio |
Coupling control factor | CCF | Coupling control factors, CCF, are flux control factors, FCF, at a constant ET-pathway competent state. |
Coupling-control ratio | CCR | Coupling-control ratios, CCR, are flux control ratios, FCR, at a constant mitochondrial pathway-control state. In mitochondrial preparations, there are three well-defined coupling states of respiration, L, P, E (LEAK, OXPHOS, Electron transfer pathway). In living cells, the OXPHOS state cannot be induced, but a ROUTINE state of respiration, R, can be measured. The reference state, J_{ref}, is defined by taking J_{ref} as the maximum flux, i.e. flux in the ET state, E, such that the lower and upper limits of the CCR are defined as 0.0 and 1.0. Then there are two mitochondrial CCR, L/E and P/E, and two CCR for living cells, L/E and R/E. |
Cytochrome c control factor | FCF_{c} | The cytochrome c control factor expresses the control of respiration by externally added cytochrome c, c, as a fractional change of flux from substrate state CHO to CHOc. In this flux control factor (FCF_{c}), CHOc is the reference state with stimulated flux; CHO is the background state with CHO substrates, upon which c is added:
FCF_{c} = (J_{CHOc}-J_{CHO})/J_{CHOc}.» MiPNet article |
ET-coupling efficiency | j_{≈E} | The ET-coupling efficiency (E-L coupling control factor) is a normalized flux ratio, j_{≈E} = ≈E/E = (E-L)/E = 1-L/E. j_{≈E} is 0.0 at zero coupling (L=E) and 1.0 at the limit of a fully coupled system (L=0). The background state is the LEAK state which is stimulated to Electron transfer pathway reference state by uncoupler titration. LEAK states L_{N} or L_{T} may be stimulated first by saturating ADP (State P) with subsequent uncoupler titration to State E. The ET-coupling efficiency is based on measurement of a coupling-control ratio (LEAK-control ratio, L/E), whereas the thermodynamic or ergodynamic efficiency of coupling between ATP production (DT phosphorylation) and oxygen consumption is based on measurement of the output/input flux ratio (~P/O_{2} ratio) and output/input force ratio (Gibbs force of phosphorylation/Gibbs force of oxidation). Biochemical coupling efficiency is either expressed as the ET-coupling efficiency, j_{≈E}, or OXPHOS-coupling efficiency, j_{≈P}, obtained in a coupling-control protocol (phosphorylation control protocol). » MiPNet article |
Ergodynamic efficiency | ε | The ergodynamic efficiency, ε (compare thermodynamic efficiency), is a power ratio between the output power and the (negative) input power of an energetically coupled process. Since power [W] is the product of a flow and the conjugated thermodynamic force, the ergodynamic efficiency is the product of an output/input flow ratio and the corresponding force ratio. The efficiency is 0.0 in a fully uncoupled system (zero output flow) or at level flow (zero output force). The maximum efficiency of 1.0 can be reached only in a fully (mechanistically) coupled system at the limit of zero flow at ergodynamic equilibrium. The ergodynamic efficiency of coupling between ATP production (DT phosphorylation) and oxygen consumption is the flux ratio of DT phosphorylation flux and oxygen flux (P»/O_{2} ratio) multiplied by the corresponding force ratio. Compare with the OXPHOS-coupling efficiency. |
Excess E-P capacity factor | j_{ExP} | The apparent excess E-P capacity factor (E-P coupling control factor), j_{ExP} = (E-P)/E = 1-P/E, is an expression of the relative limitation of OXPHOS capacity by the capacity of the phosphorylation system. j_{ExP} = 0.0 when OXPHOS is not limited by the phosphorylation system at zero Excess capacity, P=E, when the phosphorylation system does not exert any control over OXPHOS capacity. j_{ExP} increases with increasing control of the phosphorylation system over OXPHOS capacity. j_{ExP} = 1 at the limit of zero phosphorylation capacity. The OXPHOS state of mt-preparations is stimulated to Electron transfer pathway by uncoupler titration, which yields the excess E-P capacity, ExP=E-P. |
Excess E-R capacity factor | j_{ExR} | The apparent excess E-R capacity factor (E-R coupling control factor), j_{ExR} = (E-R)/E = 1-R/E, is an expression of the relative scope of increasing ROUTINE respiration in living cells by uncoupling. j_{ExR} = 0.0 for zero excess capacity when R=E; j_{ExR} = 1.0 for the maximum limit when R=0. The ROUTINE state of living cells is stimulated to Electron transfer pathway by uncoupler titration, which yields the excess E-R capacity, ExR=E-R. Since ET-capacity is significantly higher than OXPHOS capacity in various cell types (as shown by cell ergometry), ExR or j_{ExR} is not a reserve capacity available for the cell to increase oxidative phosphorylation, but strictly a scope (reserve?) for uncoupling respiration. Similarly, the apparent excess E-P capacity, ExP=E-P, is not a respiratory reserve in the sense of oxidative phosphorylation. |
Flux control factor | FCF | Flux control factors express the control of respiration by a metabolic control variable, X, as a fractional change of flux from Y_{X} to Z_{X}, normalized for Z_{X}. Z_{X} is the reference state with high (stimulated or un-inhibited) flux; Y_{X} is the background state at low flux, upon which X acts.
Complementary to the concept of flux control ratios and analogous to elasticities of metabolic control analysis, the flux control factor of X upon background Y_{X} is expressed as the change of flux from Y_{X} to Z_{X} normalized for the reference state Z_{X}. » MiPNet article |
Flux control ratio | FCR | Flux control ratios (FCR), are ratios of oxygen flux in different respiratory control states, normalized for maximum flux in a common reference state, to obtain theoretical lower and upper limits of 0.0 and 1.0 (0% and 100%). For a given protocol or set of respiratory protocols, flux control ratios provide a fingerprint of coupling and substrate control independent of (i) mt-content in cells or tissues, (ii) purification in preparations of isolated mitochondria, and (iii) assay conditions for determination of tissue mass or mt-markers external to a respiratory protocol (CS, protein, stereology, etc.). FCR obtained from a single respirometric incubation with sequential titrations (sequential protocol; SUIT protocol) provide an internal normalization, expressing respiratory control independent of mitochondrial content and thus independent of a marker for mitochondrial amount. FCR obtained from separate (parallel) protocols depend on equal distribution of subsamples obtained from a homogenous mt-preparation or determination of a common mitochondrial marker. |
Hyphenation | Hyphenation is used to connect two words (compound words) or two parts of a word to clarify the meaning of a sentence. The same two words may be hyphenated or not depending on context. Hyphenation may present a problem when searching for a term such as 'Steady state'. It is helpful to write 'steady-state measurement', to clarify that the measurement is performed at steady state, rather than implying that a state measurement is steady. But this does not imply that hyphenation is applied to the 'measurement performed at steady state'. Thus, the key word is 'steady state'. Compound adjectives should be hyphenated (steady-state measurement), but if the compound adjective follows the term (measurement at steady state), hyphenation does not add any information and should be avoided. Find more examples and guidelines in the grammarly blog on Hyphen and in apastyle.apa.org. | |
L/P coupling control ratio | L/P | The L/P coupling control ratio or LEAK/OXPHOS coupling control ratio combines the effects of coupling (L/E) and limitation by the phosphorylation system (P/E); L/P = (L/E) / (P/E) = 1/RCR. |
L/R coupling control ratio | L/R | The L/R coupling control ratio or LEAK/ROUTINE coupling control ratio combines the effects of coupling (L/E), physiological control of energy demand, and limitation by the OXPHOS capacity. |
LEAK-control ratio | L/E | The LEAK-control ratio, or L/E coupling-control ratio [1,2], is the flux ratio of LEAK respiration over ET capacity, as determined by measurement of oxygen consumption in sequentially induced states L and E of respiration. The ET-pathway control ratio is an index of uncoupling or dyscoupling at constant ET capacity. L/E increases with uncoupling from a theoretical minimum of 0.0 for a fully coupled system, to 1.0 for a fully uncoupled system [3]. |
Metabolic control variable | X | A metabolic control variable, X, causes the transition between a background state, Y_{X}, and a reference state, Z_{X}. X may be a stimulator or activator of flux, inducing the step change from background to reference steady state (Y to Z). Alternatively, X may be an inhibitor of flux, absent in the reference state but present in the background state (step change from Z to Y). |
N/NS pathway control ratio | N/NS | The N/NS pathway control ratio is obtained when succinate is added to N-linked respiration in a defined coupling state. N and NS are abbreviations for respiration in the N-pathway control state (with pyruvate, glutamate, malate, or other ETS competent N-linked substrate combinations) and the NS-pathway control state (N in combination with succinate). NS indicates respiration with a cocktail of substrates supporting the N- and S-pathways. |
NS-N pathway control factor | j_{NS-N}; j_{CI&II-CI} | The NS-N substrate control factor, j_{NS-N} = 1-N/NS, expresses the fractional change of flux when succinate is added to the N-pathway control state in a defined coupling-control state. |
NS-S control factor | j_{NS-S} | The NS-S control factor (CI&II-CII substrate control factor) expresses the relative stimulation of succinate supported respiration (S) by NADH-linked substrates (N), with the S-pathway control state as the background state and the NS-pathway control state as the reference state. In typical SUIT protocols with type N and S substrates, flux in the NS-pathway control state, NS, is inhibited by Rotenone to measure flux in the S-pathway control state, SRot or S. Then the NS-S control factor is
j_{NS-S} = (NS-S)/NSThe NS-S control factor expresses the fractional change of flux in a defined coupling-control state when inhibition by rotenone is removed from flux under S-pathway control in the presence of a type N substrate combination. Experimentally rotenone (Rot) is added to the NS-state. The reversed protocol, adding N-substrates to a S-pathway control background does not provide a valid estimation of S-respiration with succinate in the absence of Rot, since oxaloacetate accumulates as a potent inhibitor of succinate dehydrogenase (CII). |
NetOXPHOS-control ratio | ≈P/E | The netOXPHOS-control ratio (≈P/E-control ratio), ≈P/E = (P-L)/E, expresses the OXPHOS capacity (corrected for LEAK respiration) as a fraction of ET capacity. ≈P/E remains constant, if dyscoupling is fully compensated by an increase of OXPHOS capacity and free OXPHOS capacity (≈P = P-L) is maintained constant. |
NetROUTINE control ratio | ≈R/E | The netROUTINE control ratio (≈R/E control ratio), ≈R/E = (R-L)/E, expresses phosphorylation-related respiration (corrected for LEAK respiration) as a fraction of ET capacity. ≈R/E remains constant, if dyscoupling is fully compensated by an increase of ROUTINE respiration and free ROUTINE activity (≈R = R-L) is maintained constant. |
Normalization of rate | Normalization of rate (respiratory rate, rate of hydrogen peroxide production, growth rate) is required to report experimental data. Normalization of rates leads to a diversity of formats. Normalization is guided by physicochemical principles, methodological considerations, and conceptual strategies. The challenges of measuring respiratory rate are matched by those of normalization. Normalization of rates for: (1) the number of objects (cells, organisms); (2) the volume or mass of the experimental sample; and (3) the concentration of mitochondrial markers in the instrumental chamber are sample-specific normalizations, which are distinguished from system-specific normalization for the volume of the instrumental chamber (the measuring system). Metabolic flow, I, per countable object increases as the size of the object is increased. This confounding factor is eliminated by expressing rate as sample-mass specific or sample-volume specific flux, J. Flow is an extensive quantity, whereas flux is a specific quantity. If the aim is to find differences in mitochondrial function independent of mitochondrial density, then normalization to a mitochondrial marker is imperative. Flux control ratios and flux control factors are based on internal normalization for rate in a reference state, are independent of externally measured markers and, therefore, are statistically robust. | |
OXPHOS-control ratio | P/E | The OXPHOS-control ratio or P/E-coupling control ratio (OXPHOS/ET pathway; phosphorylation system control ratio) is an expression of the limitation of OXPHOS capacity by the phosphorylation system. The relative limitation of OXPHOS capacity by the capacity of the phosphorylation system is better expressed by the excess E-P capacity factor, j_{ExP} = 1-P/E. The P/E ratio increases with increasing capacity of the phosphorylation system up to a maximum of 1.0 when it matches or is in excess of ET capacity. P/E also increases with uncoupling. P/E increases from the lower boundary set by L/E (zero capacity of the phosphorylation system), to the upper limit of 1.0, when there is no limitation of P by the phosphorylation system or the proton backpressure (capacity of the phosphorylation system fully matches the ET capacity; or if the system is fully uncoupled). It is important to separate the kinetic effect of ADP limitation from limitation by enzymatic capacity at saturating ADP concentration. » MiPNet article |
OXPHOS-coupling efficiency | j_{≈P} | The OXPHOS-coupling efficiency (P-L or ≈P control factor), j_{≈P} = ≈P/P = (P-L)/P = 1-L/P. OXPHOS capacity corrected for LEAK respiration is the free OXPHOS capacity, ≈P = P-L. The OXPHOS-coupling efficiency is the ratio of free to total OXPHOS capacity. j_{≈P} = 1.0 for a fully coupled system (when RCR approaches infinity); j_{≈P} = 0.0 (RCR=1) for a system with zero respiratory phosphorylation capacity (≈P=0) or zero ET-coupling efficiency (E-L=0 when L=P=E). If State 3 is measured at saturating ADP and P_{i} concentrations (State 3 = P), then the respiratory acceptor control ratio, RCR, is P/L. Under these conditions, the RCR and OXPHOS-coupling efficiency are related by a hyperbolic function, j_{≈P} = 1-RCR^{-1}. » MiPNet article |
Pathway control factor | PCF | Pathway control factors, PCF, are flux control factors, expressing the relative change of flux in response to a transition between two Electron-transfer-pathway states due to a change of (i) substrate availability or (ii) inhibition of enzyme steps in the pathway, in a defined coupling-control state. |
Pathway control ratio | SCR | Substrate control ratios, SCR, are flux control ratios, FCR, at a constant mitochondrial coupling-control state. Whereas there are only three well-defined coupling-control states of mitochondrial respiration, L, P, E (LEAK, OXPHOS, Electron transfer pathway), numerous Electron-transfer-pathway states are possible. Careful selection of the reference state, J_{ref}, is required, for which some guidelines may be provided without the possibility to formulate general rules. FCR are best defined by taking J_{ref} as the maximum flux (e.g. NS_{E}), such that flux in various other respiratory states, J_{i}, is smaller or equal to J_{ref}. However, this is not generally possible with SCR. For instance, the N/S substrate control ratio (at constant coupling-control state) may be larger or smaller than 1.0, depending on the mitochondrial source and various mitochondrial injuries. The S-pathway control state may be selected preferentially as J_{ref}, if mitochondria with variable N-linked injuries are studied. In contrast, the reference state, Z, is strictly defined for flux control factors. |
ROUTINE coupling efficiency | j_{≈R} | The ROUTINE coupling efficiency, j_{≈R} = ≈R/R = (R-L)/R = 1-L/R, is the fraction of ROUTINE respiration coupled to phosphorylation in intact cells. ROUTINE respiration is corrected for LEAK respiration to obtain the free ROUTINE activity, ≈R. The flux control factor j_{≈R} is the free ROUTINE activity normalized for the reference state R. The background state is the LEAK state, and the flux control variable is stimulation to ROUTINE activity by physiologically controlled ATP turnover in intact cells. |
ROUTINE-control ratio | R/E | The ROUTINE-control ratio (R/E coupling control ratio) is the ratio of (partially coupled) ROUTINE respiration and (noncoupled) ET capacity. The R/E control ratio is an expression of how close ROUTINE respiration operates to ET capacity. |
Respiratory acceptor control ratio | RCR | The respiratory acceptor control ratio (RCR) is defined as State 3/State 4 [1]. If State 3 is measured at saturating [ADP], RCR is the inverse of the OXPHOS control ratio, L/P (when State 3 is equivalent to the OXPHOS state, P). RCR is directly but non-linearly related to the OXPHOS-coupling efficiency, j_{≈P} = 1-L/P. Whereas the normalized flux ratio j_{≈P} has boundaries from 0.0 to 1.0, RCR ranges from 1.0 to infinity, which needs to be considered when performing statistical analyses. In intact cells, the term RCR has been used for the ratio State 3u/State 4o, i.e. for the inverse L/E ratio [2,3]. Then for conceptual and statistical reasons, RCR should be replaced by the ET-coupling efficiency, j_{≈E}= 1-L/E [4]. |
S/NS pathway control ratio | S/NS | The S/NS pathway control ratio is obtained when rotenone (Rot) is added to the NS-pathway control state in a defined coupling control state. The reversed protocol, adding N-type substrates to a S-pathway control state as the background state does not provide a valid estimation of S-linked respiration with succinate in the absence of Rot, since oxaloacetate accumulates as a potent inhibitor of succinate dehydrogenase (CII). |
Substrate control factor | SCF | See Pathway control factor, PCF |
Substrate control ratio | SCR | See Pathway control ratio, PCR |
Uncoupling-control ratio | UCR | The uncoupling-control ratio, UCR, is the ratio of ET-pathway/ROUTINE respiration (E/R) in living cells, evaluated by careful uncoupler titrations (Steinlechner et al 1996). Compare ROUTINE-control ratio (R/E) (Gnaiger 2008). |